Antipsychotic drugs are widely prescribed to elderly patients for the treatment of a variety of psycho- pathological conditions, including psychosis and behavioral disturbances associated with cognitive impairment. However, the current treatment strategy for elderly individuals is often ineffective, with an increased incidence of sid effects. The factors contributing to reduced antipsychotic efficacy in the elderly population are not yet full understood. Induction of immediate-early genes such as c-fos has been shown to affect antipsychotic drug activity in the CNS. Both typical and atypical antipsychotics induce c Fos expression in specific brain regions, including the striatum and prefrontal cortex. Our preliminary data shows lower levels of antipsychotic induced c-Fos expression in the nucleus accumbens of aged mice, as well decreased acetylation of histone H3 lysine residue 27 (H3K27) on the c-fos promoter. Co-treatment with valproic acid (VPA), a histone deacetylase HDAC inhibitor, was shown to restore antipsychotic induced c-Fos induction and improve behavioral performance in aged mice. Our preliminary data suggests that an epigenetic mechanism may play a key role in the reduced drug efficacy seen in elderly individuals. In this study, we hypothesize that age-associated decreases in antipsychotic efficacy are the result of epigenetic changes in the brain that can be ameliorated by co-treatment with antipsychotics and HDAC inhibitors. To test our hypotheses, young (3-month old) and aged (24-month old) mice will be treated with haloperidol (HAL, a typical) or clozapine (CLZ, an atypical) alone or in combination with the HDAC1-specific inhibitor entinostat (MS-275) or pan-HDAC inhibitor VPA for 14 days. First, we will investigate the relationship between the acetylation of histone H3 lysine residue 27 (H3K27) on the c-fos promoter and antipsychotic induced c-Fos induction in the brains of aged mice using chromatin immunoprecipitation (ChIP) assays and real-time PCR. We will then examine whether increased c-Fos expression following HDAC inhibitor/antipsychotic co-treatment is specific to dopaminergic or serotoninergic neurons using immunofluorescence double labeling. Using behavioral tests relevant to memory and motor function, we will then investigate whether MS-275 treatment results in cognitive improvements similar to those seen with VPA treatment. This study will shed light on the interactions between aging, antipsychotic drug efficacy, and epigenetic regulation. By advancing our understanding of the epigenetic mechanisms of drug efficacy, it will be possible to develop new psychotropic treatment strategies that maximize benefits while minimizing side effects.